Cysteine S-conjugates may act as kidney-selective prodrugs: formation of 6-mercaptopurine by the renal metabolism of S-(6-purinyl)-L-cysteine.

The recent reports that cysteine S-conjugates of several halogenated hydrocarbons are metabolized selectively in the kidney by cysteine conjugate beta-lyase (beta-lyase) to generate thiols suggest that renal beta-lyase might be exploited for site selective delivery of sulfhydryl drugs to the kidney. In this study, the in vitro and in vivo metabolism of S-(6-purinyl)-L-cysteine, the potential precursor of the antitumor and immunosuppressant drug, 6-mercaptopurine, was examined. With renal subcellular fractions, 6-mercaptopurine was identified as a metabolite of S-(6-purinyl)-L-cysteine by its electronic absorption spectrum and by high-performance liquid chromatography. The rate of enzymatic 6-mercaptopurine formation was dependent upon incubation time, substrate and protein concentrations. Aminooxyacetic acid, an inhibitor of renal beta-lyase, inhibited the reaction. The total renal beta-lyase activity with S-(6-purinyl)-L-cysteine as substrate was distributed equally between the cytosolic and mitochondrial fractions and constituted nearly 54% of the activity measured with the prototype substrate, S-(2-benzothiazolyl)-L-cysteine. The apparent Vmax value for the mitochondrial beta-lyase-dependent metabolism of S-(6-purinyl)-L-cysteine to yield 6-mercaptopurine was 4-fold greater than the rate measured with cytosol, whereas the rates of metabolism of S-(2-benzothiazolyl)-L-cysteine by the cytosolic and mitochondrial beta-lyase were similar. When rats were given S-(6-purinyl)-L-cysteine (31.2 mg/kg i.p.) and were sacrificed at 30 min after treatments, 6-mercaptopurine, 6-methyl-mercaptopurine and 6-thiouric acid were detected in the kidney, liver or plasma.(ABSTRACT TRUNCATED AT 250 WORDS)